PDBsum entry 6fmz

Flavoprotein

PDB id: 6fmz

Contents

Protein chain

588 a.a.

Ligands

FAD

DVQ

Waters ×583

PDB id:

6fmz

Name:

Flavoprotein

Title:

Thioredoxin glutathione reductase from schistosoma mansoni in complex with 1,4-bis(2-hydroxyethyl)piperazine

Structure:

Thioredoxin glutathione reductase. Chain: a. Engineered: yes

Source:

Schistosoma mansoni. Blood fluke. Organism_taxid: 6183. Gene: smp_048430. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.80Å R-factor: 0.150 R-free: 0.178

Authors:

I.Silvestri,F.Fata,A.E.Miele,G.Boumis,D.L.Williams,F.Angelucci

Key ref:

I.Silvestri et al. (2018). Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry. ACS Chem Biol, 13, 2190-2202. PubMed id: 29800515 DOI: 10.1021/acschembio.8b00349

Date:

02-Feb-18 Release date: 06-Jun-18

Protein chain

G4V8J4  (G4V8J4_SCHMA) -

Enzyme reactions

• Enzyme class: E.C.1.8.1.9 - thioredoxin-disulfide reductase (NADPH).
• Reaction: [thioredoxin]-dithiol + NADP⁺ = [thioredoxin]-disulfide + NADPH + H⁺

[thioredoxin]-dithiol + NADP(+) (Bound ligand (Het Group name = FAD) matches with 71.19% similarity) = [thioredoxin]-disulfide + NADPH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/acschembio.8b00349

ACS Chem Biol 13:2190-2202 (2018)

PubMed id: 29800515

Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry.

I.Silvestri, H.Lyu, F.Fata, G.Boumis, A.E.Miele, M.Ardini, R.Ippoliti, A.Bellelli, A.Jadhav, W.A.Lea, A.Simeonov, Q.Cheng, E.S.J.Arnér, G.R.J.Thatcher, P.A.Petukhov, D.L.Williams, F.Angelucci.

ABSTRACT

Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off-target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectively inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms, the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases.